Rafaela Andrade-Vieira

Loss of lkb1 Expression Reduces the Latency of ErbB2-Mediated Mammary Gland Tumorigenesis, Promoting Changes in Metabolic Pathways

The tumor suppressor kinase LKB1 is mutated in a broad range of cancers however, the role of LKB1 mammary gland tumorigenesis is not fully understood. Evaluation of human breast cancer tissue microarrays, indicate that 31% of HER2 positive samples lacked LKB1 expression. To expand on these observations, we crossed STK11fl/fl mice with mice genetically engineered to express activated Neu/HER2-MMTV-Cre (NIC) under the endogenous Erbb2 promoter, to generate STK11−/−/NIC mice. In these mice, the loss of lkb1 expression reduced the latency of ErbB2-mediated tumorigenesis compared to the latency of tumorigenesis in NIC mice alone. Analysis of STK11−/−/NIC mammary tumors revealed hyperactivation of mammalian target of rapamycin (mTOR) through both mTORC1 and mTORC2 pathways as determined by the phosphorylation status of ribosomal protein S6 and AKT. Furthermore, STK11−/−/NIC mammary tumors had elevated ATP levels along with changes in metabolic enzymes and metabolites. The treatment of primary mammary tumor cells with specific mTOR inhibitors AZD8055 and Torin1, that target both mTOR complexes, attenuated mTOR activity and decreased expression of glycolytic enzymes. Our findings underscore the existence of a molecular interplay between LKB1-AMPK-mTORC1 and ErbB2-AKT-mTORC2 pathways with mTOR at its epicenter, suggestive that loss of LKB1 expression may serve as a marker for hyperactivated mTOR in HER2 positive breast cancer and warranting further investigation into therapeutics that target LKB1-AMPK-mTOR and glycolytic pathways.

Mechanisms of environmental chemicals that enable the cancer hallmark of evasion of growth suppression

As part of the Halifax Project, this review brings attention to the potential effects of environmental chemicals on important molecular and cellular regulators of the cancer hallmark of evading growth suppression. Specifically, we review the mechanisms by which cancer cells escape the growth-inhibitory signals of p53, retinoblastoma protein, transforming growth factor-beta, gap junctions and contact inhibition. We discuss the effects of selected environmental chemicals on these mechanisms of growth inhibition and cross-reference the effects of these chemicals in other classical cancer hallmarks.

Omega-3 polyunsaturated fatty acid promotes the inhibition of glycolytic enzymes and mTOR signaling by regulating the tumor suppressor LKB1

The omega-3 polyunsaturated fatty acids (ω3PUFAs) are a class of lipids biologically effective for the treatment of inflammatory disorders, cardiovascular disease and cancer. Patients consuming a high dietary intake of ω3PUFAs have shown a low incidence of metabolic disorders, including cancer. Although the effects of ω3PUFAs intake was shown to be involved in the prevention and treatment of these diseases, the underlying molecular mechanisms involved are not well understood. Here, we show that ω3PUFA, docosahexaenoic acid (DHA) enhanced the tumor suppressor function of LKB1. We observed that when LKB1 expressing cells are treated with DHA, there is an increase in LKB1 activity leading to phosphorylation of AMPK and inhibition of mTOR signaling. Abrogation of LKB1 in MCF-7 cells by siRNA reversed this phenotype. Furthermore, cellular metabolism was altered and ATP levels were reduced in response to DHA treatment, which was further attenuated in cells expressing LKB1. More importantly, in mammary epithelial cells expressing LKB1, the rate of glycolysis was decreased as a result of diminished expression of glycolytic enzymes. Functionally, these events lead to a decrease in the migration potential of these cells. Overall, our discovery shows for the first time that LKB1 function is enhanced in response to ω3PUFA treatment, thereby resulting in the regulation of cell metabolism.